The objective of the proposed research is to develop novel model systems for the study of beta-amyloid liked structures, as well as strategies for the identification of new lead compounds for the potential treatment of Alzheimer's disease. Alzheimer's disease is a progressive neurodegenerative disorder that affects approximately half of the elderly population over age 85. The preeminent neuropathological feature of Alzheimer's disease is the deposition of amyloid fibrils in the brain that result from the self-aggregative polymerization of the amyloid beta-protein (Abeta). An innovative pharmacological approach that has not yet been studied extensively for the treatment of Alzheimer's disease is to develop compounds that inhibit the formation of amyloid fibrils. The difficulties inherent to the study of insoluble beta-sheet motifs such as Abeta underscore the need for aqueous soluble, model beta-sheet macromolecular complexes. Recently, polyalanine-based peptides (Ac-KYAn K-NH2, n greater or equal to 11) have been designed by the Principal Investigator that change from "native" monomeric alpha-helical conformational states into extremely stable, aqueous soluble, macromolecular beta-pleated-sheet macrostructures. In particular, Ac-KYA13K-NH2 was found to form Abeta- like fibrils. The conformational resemblance of these polyalanine-based peptides to Abeta-like structures, and the potential neurotoxicity of the model peptides will be further studied. The model systems will then be used for the identification of inhibitors of beta-sheet macrostructure formation. This will be accomplished by screening synthetic combinatorial libraries (SCLs) made up of thousands to millions of heterocyclic compounds, peptidomimetics, or peptides. The SCL approach allows the rapid identification of highly active compounds from large pools of individual compounds. In an initial step, an assay will be developed that will allow large numbers of samples to be assayed simultaneously. Both biophysical techniques (e.g., size exclusion chromatography, circular dichroism, and fluorescence) and colorimetric techniques (e.g., MTT reduction assay) will be evaluated. The activity of the identified inhibitory compounds will then be determined against short derivatives of Abeta (i.e., beta1-39) in order to confirm the utility and generality of the approach. The results of these studies are anticipated to have significant value as a potential strategy for the prevention of beta-amyloid formation.